A desmosome is a structure that forms a site of adhesion between two adjacent cells, and comprises a dense plate in each adjacent cell separated by a thin layer of extracellular material. The desmosome further comprises a molecular complex of cellular adhesion proteins and linking proteins that append the cell surface adhesion proteins to intracellular keratin cytoskeletal filaments within a cell. Thus, the basic components of the desmosome are the desmosomal plaque and the associated transmembrane adhesion molecules which function to connect neighboring desmosomes. When the desmosomes that connect adjacent epithelial cells do not function properly, epidermal skin layers can pull apart to allow abnormal movements of fluid within the skin, which can result in blisters and other tissue damage.
In a subject afflicted with an autoimmune disorder, the immune system typically does not distinguish between the subject's own antigens and foreign antigens, resulting in recognition of autologous tissues or soluble molecules as if they were foreign. Subsequent immune responses to the autologous cells or tissue can cause autologous tissue destruction or inflammatory reactions normally reserved for foreign organisms, pathogens, cells or tissue. In autoimmune bullous disorders, one or more components of the desmosome can become the target of specific autoantibodies and thus trigger expansion of the disorder. One particular example of an autoimmune bullous disorder is pemphigus vulgaris, a disorder in which antibodies to the transmembrane protein desmoglein 3 (dsg3) play a role in the disruption of desmosomes and ultimately cell-cell detachment, resulting in the formation of intraepidermal clefts, vesicles or bullae (which can be collectively referred to herein as “blisters”).
To elaborate, pemphigus vulgaris is an uncommon, potentially fatal, autoimmune skin disorder characterized by the presence of bullae on apparently healthy skin and mucus membranes wherein a patient's own circulating antibodies attack the points of adhesion of epithelial cells and mucous membranes. The primary lesions associated with pemphigus vulgaris often occur first in the mouth, where they soon rupture and remain as chronic, often painful, erosions for variable periods of time before the skin is affected. On the skin, the bullae typically arise to leave a raw, denuded area and crusting upon rupture. In human pemphigus vulgaris disorders, pathogenic antibodies bind the desmosomal cadherein protein desmoglein-3 (dsg3) causing epidermal cell-cell detachment, ultimately resulting in blisters on the associated tissue.
There are limited treatment options for many blistering disorders (including pemphigus vulgaris). Methods of treatment currently employed in the art include heavy doses of corticosteriods and azathioprine, with relapses common after therapy is stopped. Secondary infection is frequent due to the immune suppression associated with these drugs. Further, these drugs have limited efficacy, toxic side effects, and tend to induce a global immunosuppression. Thus, additional and/or more effective treatment options represent a long-felt and ongoing need in the art.